Novel mutations in the USH2A gene in a family affected with Usher syndrome type 2_Chinese Journal of Ocular Fundus Diseases

Authors：

Cheng Meng , Yang Ge , Lei Bo , Liu Yuying ,  Jin Xuemin

Department of Ophtalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China (Cheng Meng, Yang Ge, Lei Bo, Liu Yuying, Jin Xuemin); Henan Eye Institute & Henan Eye Hospital, Henan Provincial People's Hospital, Zhengzhou 450003, China (Lei Bo, Jin Xuemin);

Corresponding author：

Jin Xuemin, Email: 2740913223@qq.com

Keywords：

Usher syndromes/genetics; Usher syndromes/etiology; Genes; Mutation; Sequence analysis

DOI：

10.3760/cma.j.issn.1005-1015.2018.03.014

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

ObjectiveTo identify the pathogenic genes and mutations in a family with Usher syndrome type 2.MethodsA three-generation family including 7 individuals was enrolled in this study. There were 2 male patients and 5 unaffected individuals. All participants was underwent related ophthalmologic examination, including best corrected visual acuity, slit-lamp, indirect ophthalmoscopy, electroretinogram (ERG), optical coherence tomography and visual field test. DNA was extracted from 3 ml peripheral venous blood of all participants. A total of 136 hereditary retinal disease target genes were screened and the DNA sequence was performed by Next-generation sequence analysis. Then the suspected mutations compared with databases to identify the suspected mutations, which should be verified with non-affected family members and 100 normal subjects by PCR and Sanger sequence.ResultsThe sequence result showed that 2 patients, the proband and his brother, carried complex heterozygous mutations in the USH2A gene: c.5459T＞C (p.M1820T) in exon 27, c.802G＞A (p.G268R) in exon 5 and c.1190T＞A (p.I397K) in exon 7. The c.5459T＞C and c.1190T＞A mutations in USH2A have not been reported in the literature and database. Although their mother carried c.5459T＞C (p.M1820T) and c.802G＞A (p.G268R), and their father carried c.1190T＞A (p.I397K) heterozygous mutations, the parents did not present phenotype. These mutations were not detected in other normal family members. The result was supported by co-segregation analysis.ConclusionThe heterozygous mutations c.5459T＞C (p.M1820T), c.1190T＞A (p.I397K) and c.802G＞A (p.G268R) in USH2A gene cause Usher syndrome in this family.

Citation： Cheng Meng, Yang Ge, Lei Bo, Liu Yuying, Jin Xuemin. Novel mutations in the USH2A gene in a family affected with Usher syndrome type 2. Chinese Journal of Ocular Fundus Diseases, 2018, 34(3): 268-271. doi: 10.3760/cma.j.issn.1005-1015.2018.03.014 Copy

1.	Boughman JA, Vernon M, Shaver KA. Usher syndrome: definition and estimate of prevalence from two high-risk populations [J]. J Chronic Dis, 1983, 36(8): 595-603.
2.	Millán JM, Aller E, Jaijo T, et al. An update on the genetics of usher syndrome [J/OL]. J Ophthalmol, 2011, 2011:417217[2011-12-23]. http://dx.doi.org/10.1155/2011/417217. DOI: 10.1155/2011/417217.
3.	Vache C, Besnard T, le Berre P, et al. Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy [J]. Hum Mutat, 2012, 33(1): 104-108. DOI: 10.1002/humu.21634.
4.	Keats BJ, Corey DP. The usher syndromes [J]. Am J Med Genet, 1999, 89(3): 158-166.
5.	Dreyer B, Brox V, Tranebjaerg L, et al. Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type Ⅱ[J]. Hum Mutat, 2008, 29(3): 451. DOI: 10.1002/humu.9524.
6.	Weston MD, Eudy JD, Fujita S, et al. Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type Ⅱa [J]. Am J Hum Genet, 2000, 66(4): 1199-1210.
7.	Lentz J, Keats B. Usher syndrome type Ⅱ [DB/OL]//Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews^®. Seattle (WA): University of Washington,1999(2016-07-21)[2018-05-02].https://www.ncbi.nlm.nih.gov/books/NBK1341/.
8.	Weston MD, Luijendijk MW, Humphrey KD, et al. Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type Ⅱ [J]. Am J Hum Genet, 2004, 74(2): 357-366.
9.	Ebermann I, Scholl HP, Charbel Issa P, et al. A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss [J]. Hum Genet, 2007, 121(2): 203-211. DOI: 10.1007/s00439-006-0304-0.
10.	Sankila EM, Pakarinen L, Kaariainen H, et al. Assignment of an Usher syndrome type III (USH3) gene to chromosome 3q [J]. Hum Mol Genet, 1995, 4(1): 93-98.
11.	Eisenberger T, Slim R, Mansour A, et al. Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3 [J]. Orphanet J Rare Dis, 2012, 7: 59. DOI: 10.1186/1750-1172-7-59.
12.	Puffenberger EG, Jinks RN, Sougnez C, et al. Genetic mapping and exome sequencing identify variants associated with five novel diseases [J/OL]. PLoS One, 2012, 7(1): 28936 [2012-01-17]. https://doi.org/10.1371/journal.pone.0028936. DOI: 10.1371/journal.pone.0028936.
13.	Ebermann I, Phillips JB, Liebau MC, et al. PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome [J]. J Clin Invest, 2010, 120(6): 1812-1823. DOI: 10.1172/JCI39715.
14.	Khateb S, Zelinger L, Mizrahi-Meissonnier L, et al. A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome [J]. J Med Genet, 2014, 51(7): 460-469. DOI: 10.1136/jmedgenet-2014-102287.
15.	Miyagawa M, Naito T, Nishio SY, et al. Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients [J/OL]. PLoS One, 2013, 8(8): 71381[2013-08-13]. https://doi.org/10.1371/journal.pone.0071381. DOI: 10.1371/journal.pone.0071381.

1. Boughman JA, Vernon M, Shaver KA. Usher syndrome: definition and estimate of prevalence from two high-risk populations [J]. J Chronic Dis, 1983, 36(8): 595-603.
2. Millán JM, Aller E, Jaijo T, et al. An update on the genetics of usher syndrome [J/OL]. J Ophthalmol, 2011, 2011:417217[2011-12-23]. http://dx.doi.org/10.1155/2011/417217. DOI: 10.1155/2011/417217.
3. Vache C, Besnard T, le Berre P, et al. Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy [J]. Hum Mutat, 2012, 33(1): 104-108. DOI: 10.1002/humu.21634.
4. Keats BJ, Corey DP. The usher syndromes [J]. Am J Med Genet, 1999, 89(3): 158-166.
5. Dreyer B, Brox V, Tranebjaerg L, et al. Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type Ⅱ[J]. Hum Mutat, 2008, 29(3): 451. DOI: 10.1002/humu.9524.
6. Weston MD, Eudy JD, Fujita S, et al. Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type Ⅱa [J]. Am J Hum Genet, 2000, 66(4): 1199-1210.
7. Lentz J, Keats B. Usher syndrome type Ⅱ [DB/OL]//Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews^®. Seattle (WA): University of Washington,1999(2016-07-21)[2018-05-02].https://www.ncbi.nlm.nih.gov/books/NBK1341/.
8. Weston MD, Luijendijk MW, Humphrey KD, et al. Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type Ⅱ [J]. Am J Hum Genet, 2004, 74(2): 357-366.
9. Ebermann I, Scholl HP, Charbel Issa P, et al. A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss [J]. Hum Genet, 2007, 121(2): 203-211. DOI: 10.1007/s00439-006-0304-0.
10. Sankila EM, Pakarinen L, Kaariainen H, et al. Assignment of an Usher syndrome type III (USH3) gene to chromosome 3q [J]. Hum Mol Genet, 1995, 4(1): 93-98.
11. Eisenberger T, Slim R, Mansour A, et al. Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3 [J]. Orphanet J Rare Dis, 2012, 7: 59. DOI: 10.1186/1750-1172-7-59.
12. Puffenberger EG, Jinks RN, Sougnez C, et al. Genetic mapping and exome sequencing identify variants associated with five novel diseases [J/OL]. PLoS One, 2012, 7(1): 28936 [2012-01-17]. https://doi.org/10.1371/journal.pone.0028936. DOI: 10.1371/journal.pone.0028936.
13. Ebermann I, Phillips JB, Liebau MC, et al. PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome [J]. J Clin Invest, 2010, 120(6): 1812-1823. DOI: 10.1172/JCI39715.
14. Khateb S, Zelinger L, Mizrahi-Meissonnier L, et al. A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome [J]. J Med Genet, 2014, 51(7): 460-469. DOI: 10.1136/jmedgenet-2014-102287.
15. Miyagawa M, Naito T, Nishio SY, et al. Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients [J/OL]. PLoS One, 2013, 8(8): 71381[2013-08-13]. https://doi.org/10.1371/journal.pone.0071381. DOI: 10.1371/journal.pone.0071381.

Chinese Journal of Ocular Fundus Diseases

Novel mutations in the USH2A gene in a family affected with Usher syndrome type 2

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content